Current Nutrition Reports (2021) 10:47–57

https://doi.org/10.1007/s13668-020-00347-9

MATERNAL AND CHILDHOOD NUTRITION (AC WOOD, SECTION EDITOR)

Artificial Pancreas Technology Offers Hope for Childhood Diabetes

Melissa J. Schoelwer 1 & Mark D. DeBoer 1

Accepted: 20 December 2020 / Published online: 7 January 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

Abstract
Purpose of Review Here, we provide a review of recent advancements in closed-loop or automated insulin delivery systems
commonly referred to as the “artificial pancreas” (AP) for the management of type 1 diabetes (T1D).
Recent Findings The use of hybrid closed-loop devices in children and adolescents with T1D consistently increases time in the
target glucose range (70–180 mg/dL) without increasing the risk of hypoglycemia. Although hybrid closed-loop systems are able
to maintain fairly tight glycemic control overnight, daytime control remains challenging, primarily due to meals and exercise, and
careful carbohydrate counting and meal boluses remain essential components of optimal diabetes control. Bihormonal and fully
automated AP systems remain investigational at this time.
Summary While commercially available hybrid closed-loop AP systems improve glycemic control in children with T1D, more
work is needed to achieve a fully automated AP system and decrease the burden of using diabetes technology.

Keywords Artificial pancreas . Type 1 diabetes . Closed-loop control . Automated insulin delivery . Pediatric

Introduction limiting exposure to hypoglycemia. The benefits of intensive

Type 1 diabetes (T1D) is an autoimmune disease that results
in destruction of the pancreatic islet cells and the inability to
produce insulin, an essential hormone for glucose metabolism.
T1D often presents in childhood and the incidence appears to
be rising worldwide [1]. The management of T1D is compli-
cated and is centered on frequent monitoring of blood glucose,
careful carbohydrate counting, and subcutaneous insulin ad-
ministration. Insulin can be administered either with multiple
daily subcutaneous injections with a syringe or a pen device or
via continuous infusion with an insulin pump, a device worn
outside the body that infuses rapid-acting insulin through a
subcutaneous cannula that is inserted every 2–3 days.
The primary goal of diabetes management is to prevent the
development of macro- and microvascular complications such
as cardiovascular disease, retinopathy, nephropathy, and neu-
ropathy by achieving near-normal glycaemia while also
management for the prevention of long-term complications
were first demonstrated in the landmark Diabetes Control
and Complications Trial (DCCT) published in 1993 [2].
Glycemic targets for children with T1D have become more
rigorous over time, and the HbA1c goal is now < 7%
(53 mmol/mol) for all children regardless of age [3, 4].
While the majority of children with T1D are unable to meet
the HbA1c target with current therapies [5•], advancements in
the field of diabetes technology have shown significant prom-
ise in improving glycemic control and decreasing the burden
of diabetes management. The remainder of this review will
focus on closed-loop control or automated insulin delivery
technology, otherwise commonly referred to as “artificial pan-
creas” (AP) systems.
Search Strategy and Selection Criteria

This article is part of the Topical Collection on Maternal and Childhood A PubMed search was done using the terms “artificial pancre-
Nutrition as,” “closed-loop control,” or “automated insulin delivery” in
combination with “type 1 diabetes.” The search was limited to
* Mark D. DeBoer the past 5 years (2015–present). Articles were chosen for in-
deboer@virginia.edu
clusion based on study design and applicability to this review
1
Division of Pediatric Endocrinology and Center for Diabetes
with preference given to pediatric studies and pivotal trials
Technology, University of Virginia, 1215 Lee Street, resulting in FDA-approved AP systems. Relevant literature
Charlottesville, VA 22903, USA was also obtained from the reference lists of chosen articles.
48
Artificial Pancreas Basics
There are three key components of an AP system: an insulin
pump, a continuous glucose monitor (CGM) or “sensor,” and
a control algorithm. The majority of AP systems use insulin
only; however, dual-hormone devices are also under investi-
gation, primarily with the addition of glucagon. The algorithm
uses information from the CGM (current glucose and glucose
rate of change) along with the calculated insulin on board
(active insulin) to automatically adjust insulin delivery to keep
the blood glucose within a desired target range [6]. AP sys-
tems that are presently commercially available are considered
hybrid closed-loop (HCL) systems as they still require that the
user count and enter the grams of carbohydrates consumed
with each meal or snack for optimal performance.
Additional input about exercise and sleep might also be en-
tered depending on the system. In contrast, a fully closed-loop
system would not require any input from the user about meals
or exercise.
Continuous Glucose Monitors
The development of accurate CGM devices over the past
20 years was crucial for the advancement of AP technology.
CGM are inserted under the skin and are typically worn for 7–
14 days depending on the device. They measure glucose in the
interstitial fluid rather than in the blood, which results in a 5–
10-min delay when comparing with a blood glucose reading.
The accuracy of commercial sensors is measured by the mean
absolute relative difference (MARD), which compares a sen-
sor reading with a blood glucose measurement [7]. Accuracy
has improved significantly over time. Early sensors required
multiple daily calibrations with a blood glucose meter value to
increase precision. However, many current sensors have a
MARD < 10%, a threshold that is largely considered accurate
enough to make insulin dosing decisions, with few to no cal-
ibrations needed [8].
The data from some CGM can be wirelessly transmitted to
another device such as a smartphone or insulin pump for 24-h
real-time monitoring of glucose trends, a feature particularly
appreciated by parents of children with T1D. CGM use has
increased dramatically in the pediatric age range over the last
few years, especially in children under the age of 12 years [5•].
The use of CGM is associated with improved glycemic out-
comes, regardless of insulin delivery modality used for diabe-
tes management, along with a reduction in severe hypoglyce-
mia and diabetic ketoacidosis [5, 9]. At the time of this pub-
lication, there are four CGM devices commercially available
in the USA: the Medtronic Guardian 3, the Dexcom G6, the
long-term implantable Senseonics Eversense, and a flash
CGM known as the Freestyle Libre.
Curr Nutr Rep (2021) 10:47–57
CGM-based glycemic outcomes are now widely reported
in the AP literature to detect improvements in glycemic con-
trol outside of the customary HbA1c. Clinical targets for
CGM-based outcomes were recently published, with the goal
time in range (TIR, 70–180 mg/dL) set to ≥ 70% and time
spent in hypoglycemia (< 70 mg/dL) to ≤ 4% [10].
Control Algorithms
The control algorithms used in AP systems take into ac-
count various inputs including CGM data, insulin param-
eters programmed into the pump, total daily insulin, and
insulin on board and use predictive models to guide insu-
lin dosing decisions. Three different control strategies
have been employed in AP systems: proportional, inte-
gral, derivative (PID) control, model predictive control
(MPC), and fuzzy logic (FL) [6, 11]. A PID algorithm
adjusts basal insulin delivery in response to real-time glu-
cose readings to the target glucose whereas a MPC algo-
rithm adjusts insulin delivery based on its prediction of a
future blood glucose value. A controller using FL also
uses CGM data but tries to imitate clinical decisions when
altering insulin dosing. Each control algorithm is unique
and most controllers use a combination of these tech-
niques. Early control algorithm platforms were indepen-
dently located on a computer or smartphone, wirelessly
receiving data from the CGM and communicating with
the insulin pump. Over time, these controllers have been
integrated into insulin pumps, allowing for greater sim-
plicity and improved connectivity.
Artificial Pancreas Development
First-Generation Systems
The first commercially available AP systems focused solely
on limiting hypoglycemia, which is a significant concern for
patients with T1D, particularly overnight [12]. The Medtronic
530G Threshold Suspend pump released in 2013 stopped in-
sulin delivery during times of hypoglycemia, referred to as
low glucose suspend (LGS) system [13, 14]. This was quickly
followed by the ability to stop or decrease insulin delivery
prior to the development of frank hypoglycemia, known as
predictive low glucose suspend (PLGS). The Medtronic
640G became available in 2015 [15, 16] followed by
Tandem Basal-IQ in 2018 [17], both of which utilize PLGS
algorithms. These devices were found to be effective in
preventing hypoglycemia without increasing hyperglycemia
and marked a significant milestone in automated insulin de-
livery [17, 18].
Curr Nutr Rep (2021) 10:47–57
FDA-Approved Hybrid Closed-Loop Systems
Two hybrid closed-loop systems are commercially available
in the USA at the time of this report, the Medtronic 670G and
the Tandem Control-IQ. Key similarities and differences of
these systems are outlined in Table 1.
Medtronic 670G
The Medtronic MiniMed 670G system, consisting of the
MiniMed 670G insulin pump, the Guardian 3 CGM, and a
“SmartGuard” algorithm, was the first on the market in 2018
and is now approved by the FDA for use in patients down to
7 years of age [19]. When in auto mode, the system adjusts
basal insulin delivery every 5 min, targeting blood glucose of
120 mg/dL. While it requires programming with standard
pump parameters such as carbohydrate ratios and correction
factors, it uses total daily insulin over the preceding 2–6 days
to determine these parameters while in auto mode. The
Guardian sensor requires at least 2 calibrations each day, al-
though 3–4 calibrations per day are recommended for greatest
accuracy, and can be worn for up to 7 days.
A number of feasibility, safety, and efficacy trials led up to
the phase 3 outpatient pivotal trials resulting in FDA approval
of this device. The first multicenter pivotal trial published by
Garg et al. in 2017 demonstrated increased TIR in adolescents
and adults using the system in auto mode for 3 months com-
pared to 2 weeks of use in manual mode [20]. Notably in that
trial, adolescents experienced more difficulty staying in auto
mode than adults (75.8 vs. 88%, respectively).
Forlenza and colleagues published the second multicenter
pivotal trial in 2019 in children 7–13 years of age, also done
Table 1 Comparison of FDA-approved artificial pancreas systems
Medtronic 670G
Ages approved 7 years and older
Control algorithm PID
CGM used Guardian 3
Basal insulin delivery Calculated every 5 min, irrespective
of programmed rate
Automated corrections No
Manual corrections Calculated by algorithm
Target range 120 mg/dL
Active insulin time Can be programmed
Exercise mode feature No
Sleep mode feature No
Remote monitoring No
capability
49
over the course of 3 months [21••]. The mean TIR achieved in
this trial was 65%, which was a significant increase from
baseline. Additionally, less time in hypoglycemia and a lower
HbA1c was reported with use of the system. Auto mode was
in use 81% of the time during this study.
Since FDA approval, a number of studies have been con-
ducted on real-world outcomes using the Medtronic 670G
system. Stone et al. reported an increase in TIR in users in
auto mode compared to manual mode (73.3 vs. 66.0%) [22].
Despite encouraging reports of improved glycemic outcome,
discontinuation of the system appears to be fairly common,
particularly in adolescents. One study in children noted a 37%
discontinuation rate over the course of 6 months along with a
decrease in time spent in auto mode and sensor wear over time
[23]. It is likely that the burden of wearing multiple devices
and keeping the technology connected contributes to AP
discontinuation.
Only one publication of the use of the Medtronic 670G
system was found in children under the age of 7 years, a
retrospective review of 16 children (average age 4.3 years)
at one center using the device off-label for 3–12 months
[24]. The authors reported a significant increase in TIR when
using auto mode from 42.8 to 56.2% along with a reduction in
HbA1c (7.9 vs. 7.4%); however, significantly more time was
spent in hypoglycemia (1.3 vs. 2.4%).
Tandem Control-IQ
The second FDA-approved hybrid closed-loop system is
known as Tandem Control-IQ, which combines a Tandem
t:slim X2 pump with the Dexcom G6 CGM. Unique features
of this system include its ability to give automated correction
Tandem Control-IQ Medtronic 770G
6 years and older 2 years and older
MPC PID
Dexcom G6 Guardian 3
Modified based on programmed basal rate Calculated every 5 min, irrespective
of programmed rate
Yes No
Uses programmed correction factor Calculated by algorithm
112.5–160 mg/dL depending on mode 120 mg/dL
Automatically set to 5 h, cannot be changed Can be programmed
Yes No
Yes No
Yes Yes
50 Curr Nutr Rep (2021) 10:47–57

boluses in addition to modifying basal insulin delivery as well
as intensifying glucose control overnight through a lower tar-
get when in “sleep mode.”
Large randomized clinical trials of the Control-IQ system
were recently published in children, adolescents, and adults,
demonstrating an increase in TIR compared to standard
therapy (sensor-augmented pump) in all age groups studied
[25, 26]. Adolescents and adults with T1D increased TIR
from 61 ± 17% at baseline to 71 ± 12% over the course of
6 months. In addition, mean HbA1c was significantly lower
(− 0.33%) in the closed-loop group compared to the control
group using sensor-augmented pumps after 6 months of use.
Similar findings were reported in children 6–12 years of age
who achieved a mean TIR of 67 ± 10% over 16 weeks of
treatment with Control-IQ compared to 55 ± 13% in the
control group (Fig. 1). Importantly, time in closed-loop in
both of these studies was high (> 90%).
Real-world data of use of the Control-IQ system in 1435
participants aged 14 years and older was recently published
and documented improvements both in glycemic and psycho-
social outcomes [27]. In addition to high TIR on Control-IQ
over the 1-month study (median TIR 78.2% and 79.2% at each
study point), the participants reported high satisfaction and
trust in the system.
Medtronic 770G
The FDA recently approved the Medtronic 770G system in
September 2020 and it is expected to be commercially

Fig. 1 Percent time-in-target-

range (TIR) during a randomized
controlled trial (RCT) of an
artificial pancreas (AP) system vs.
usual care among school-aged
children age 6–12 years. Data
shown are from an RCT of the
Tandem Control-IQ system
demonstrating increased TIR 70–
180 mg/dL throughout the study
(a). This increase in TIR was
driven by improvements
overnight, a strength of AP
systems compared to usual care.
From N Engl J Med 2020;
383:836–845, used by permission
Curr Nutr Rep (2021) 10:47–57
available by the time of this publication. Updated features
include the ability to monitor CGM data remotely using a
smartphone app and the ability to do software updates to the
algorithm directly onto the pump, features that are also present
in the Control-IQ system. CGM calibrations continue to be
recommended 2–4 times daily for this system. While it is
approved down to 2 years of age, there is a minimum total
daily insulin requirement of 8 units.
The follow-up to the 770G, known as the 780G, is already
under development as well. There are a few reports in the
literature of “enhanced HCL” Medtronic systems that have
tested out several iterations of the upgraded algorithm [28].
A small, 1-month feasibility trial in 12 adults showed that TIR
increased (85.3 vs. 75% at baseline) but time spent in hypo-
glycemia also increased (4.4 vs. 3%) [28]. Time spent in
closed loop was high with few auto mode exits, a significant
improvement over the 670G experience. A small camp study
in adolescents reported similar TIR between users of the 670G
and an enhanced HCL system, although there were fewer auto
mode exits and alarms in the experimental group [29]. Similar
findings were reported in a small adult study using an en-
hanced system [30].
“Do-It-Yourself” Artificial Pancreas Systems
Over the past 5–10 years, multiple “Do-It-Yourself” (DIY)
artificial pancreas systems have become available through
open-source platforms [31]. These systems utilize existing
CGM and insulin pump products and connect them using
computer algorithms on a smartphone to create a closed-
loop system. The design of these systems has been driven in
large part by impatience among individuals in the T1D com-
munity with the long time required for regulatory approval for
commercially available AP systems, as well as a desire to
individualize therapy for a user’s needs [32]. Unlike tradition-
al research-based approaches that require oversight by the
FDA and other regulatory agencies, these DIY systems have
not had the same degree of rigorous testing and do not require
reporting of adverse events, leaving the safety of these sys-
tems less clear.
In observational studies, parents who have chosen to use
these systems for insulin management in their children express
a high degree of satisfaction, and pre-/post-assessments of
glycemic control on these systems compared to prior manage-
ment for individual users have reported a higher degree of TIR
and less hypoglycemia [31, 33, 34]. One study reported an
improvement in HbA1c among users from 6.91 to 6.27%
(p < 0.001) and in TIR from 64.2 to 80.7% [33]—demonstrat-
ing that in many cases, families using DIY systems were al-
ready well controlled before use.
It should be noted that most available data on DIY efficacy
are self-reported and that randomized trials of these systems or
51
control groups are lacking [31]. In addition, the majority of
articles reporting about DIY systems combine multiple types
of DIY systems, though each system likely has different levels
of safety, efficacy, and acceptability. The lack of regulation of
these devices is particularly cogent to their use in children who
in most cases do not have a complete understanding of the
potential risks. It is also possible that there may be a lower
degree of willingness among families using these devices to
report negative outcomes or adverse events given the stakes of
providing untested algorithms for use in their children. With
recent and on-going approval of commercially available AP
systems, it remains unclear whether DIY systems will contin-
ue in use or whether the majority of users will opt for FDA-
approved systems.
Artificial Pancreas Systems
Under Development
There are multiple other insulin-only HCL AP systems that
are under development and are being studied in clinical trials.
Insulet has been testing an AP algorithm for use in the
Omnipod patch insulin pump, which is a popular pump brand
in young children, as it does not have tubing. Pivotal trials for
this system are underway, but it is not FDA approved at the
time of this report. Lily, Inc., has also published data from a
trial of an AP system developed by their company. A summa-
ry of selected AP studies over the past 3 years, both those that
are commercially available and under development, is pre-
sented in Table 2.
Dual-Hormone Artificial Pancreas Systems
While the majority of AP systems have focused solely on
modulating insulin delivery to achieve improvements in
TIR, a smaller number of systems have been developed that
infuse other hormones in addition to insulin. The most preva-
lent of these is glucagon, which is used to raise glucose levels
acutely to avoid hypoglycemia. Damiano et al. from Boston
University developed such a system that has been reported in
multiple pediatric trials [35, 36]. These systems utilized a
Dexcom CGM sensor that sends signals to a smartphone run-
ning the AP controller, which then sent infusion commands to
two separate insulin pumps—one delivering insulin and one
glucagon. The studies reported thus far utilized a preparation
of glucagon that had to be replaced daily.
One of these dual-hormone studies evaluated adolescents
12–20 years old at a diabetes summer camp and was com-
pared to usual care, each used for 5 days in a randomized
crossover study design [35]. On the dual-hormone system,
TIR increased to 75.9% ± 7.9 from 64.5% ± 14 (p < 0.001)
on usual care without significant change in time < 70 (6.1%
and 7.6%). During dual-hormone AP use, adolescents
52 Curr Nutr Rep (2021) 10:47–57

Table 2 Review of select AP literature published within the past 3 years

Study AP system Study design Population Study length Results

Single hormone
Ekhlaspour et al. Tandem RCT N = 48 2-day ski camp Higher TIR in HCL group (66.4 vs. 53.9%) during
(2019) [52] Control-IQ Age 6–18 years intensive winter sport activities. Rates of
hypoglycemia were similar between both
groups.
Forlenza et al. Tandem RCT N = 24 3 days TIR was higher in the HCL group (71 vs. 52.8%)
(2019) [53] Control-IQ Age 6–12 years with similar rates of hypoglycemia.
Brown et al. Tandem RCT N=168 6 months TIR was higher in the HCL group compared to
(2019) [25••] Control-IQ Age 14–71 years control group (71 vs. 61%). Time in closed loop
was 90%.
Schoelwer et al. Tandem RCT N = 18 1 week Initializing HCL with simple “MyTDI”
(2020) [54] Control-IQ Age 12–18 years parameters based on total daily insulin resulted
in similar TIR as using home insulin pump
parameters in adolescents
Breton et al. Tandem RCT N = 101 4 months Mean TIR was higher in HCL than the control
(2020) [26••] Control-IQ Age 6–13 years group (67 vs. 55%). Median percentage of time
in closed loop was 93%.
Pinsker et al. Tandem Observational N = 1435 1 month Real-world use of Control-IQ showed most
(2020) [27] Control-IQ Mean age participants met CGM goal of > 70% TIR with
45.5 years only 1.7% hypoglycemia. Median TIR was
78.2% at T1 and 79.2% at T2.
Kovatchev et al. Tandem Randomized N = 80 8 months Use of HCL only in the evenings and overnight
(2020) [55] Control-IQ crossover Age 18–69 years reduced hypoglycemia compared to SAP and
achieved most of the glycemic benefits of 24-7
HCL
Forlenza et al. Medtronic 670G Observational N = 105 3 months At the end of the study, HbA1c decreased from 7.9
(2019) [21••] Age 7–13 years to 7.5% and TIR increased from 56.2 to 65%.
Median use of auto mode was 81%.
Lal et al. (2019) Medtronic 670G Observational N = 79 12 months Auto mode use was associated with lower HbA1c;
[56] Age 9–61 years however, 33% of 670G users discontinued use
by 12 months.
Messer et al. Medtronic 670G Observational N = 92 6 months 30% discontinued use of HCL by the end of the
(2020) [57] Age 8–25 years study. Higher baseline HbA1c predicted
discontinuation.
Berget et al. Medtronic 670G Observational N = 92 6 months TIR increased from 50.7% at baseline to 56.9%
(2020) [23] Mean age and HbA1c decreased from 8.7 to 8.4% at
15.7 ± 3.6 years 6 months; however, use of auto mode
decreased over time (only 51.2% at 6 months).
de Bock (2018) Medtronic RCT N = 12 1 week camp TIR was not significantly different between the
DTT [29] Enhanced HCL Age 13–17 years control group (standard 670G) and the e-HCL
users (75.85 vs.74.32%). There were 2.1
alarms/day in the control group compared to
0.26 in experimental group. Auto mode exits
were less frequent in the experimental group.
Lee et al. (2019) Medtronic Observational N = 12 1 week supervised TIR was higher with use of the e-HCL (85.3 vs.
[28] Enhanced HCL Median age hotel followed 75%). Time < 70 mg/dL also increased (4.4 vs.
48 years by 3 weeks of 3%). Time in closed loop was high (99.98%).
home use
Paldus et al. Medtronic Randomized N = 11 2 weeks TIR and mean glucose favored e-HCL but did not
(2019) [30] Enhanced HCL crossover reach statistical significance. e-HCL use
significantly decreased CL exits and alerts.
Tauschmann Cambridge RCT N = 86 3 months TIR was higher in the HCL group compared to the
et al. (2018) FlorenceM Age 6 years and control group (65% vs. 54%) and HbA1c was
[42] older (median lower (7.4% vs. 7.7%)
age 21 years)
Tauschmann Cambridge Randomized N = 24 6 weeks No difference in TIR when using closed loop with
et al. (2019) FlorenceM crossover Age 1–7 years standard insulin vs. diluted insulin (70 vs. 72%)
[58]
Curr Nutr Rep (2021) 10:47–57 53

Table 2 (continued)

Study AP system Study design Population Study length Results

Buckingham Omnipod Horizon Observational N = 12 54 h, supervised Safety of algorithm documented during

et al. (2018) Mean age hotel overestimated, missed, and extended meal
[59] 35.4 years boluses.
Buckingham Omnipod Horizon Observational N = 58 36 h, inpatient Primary safety endpoints of hypoglycemia
et al. (2018) Age 6–65 years < 70 mg/dL: 2% in children and adolescents.
[60] TIR during HCL was 72.6% for adolescents
and 70.1% for children.
Forlenza et al. Omnipod Horizon Observational N = 12 54-h supervised Subjects completed two > 30 min moderate
(2019) [61] Mean age hotel intensity exercise activities. Mean TIR was
36.5 years 85.1% with 1.4% time spent < 70 mg/dL (no
hypoglycemia overnight).
Sherr et al. (2020) Omnipod Horizon Observational N = 36 5 days, supervised TIR increased significantly for adolescents (79 vs.
[62] Age 8–48 years hotel 60.6%) and children (69.2 vs. 54.9%) compared
to standard therapy
Ekhlaspour et al. Bionic Pancreas Observational N = 13 3 weeks TIR 69% for static set-point and 72% for dynamic
(2019) [63] Age 19–37 years set-point (not significantly different)
Christiansen Lilly HCL Observational N = 20 3 days TIR on the system was 81.2% overall, 85.2%
(2020) [64] Mean age outside of challenges (meal and exercise), and
44.7 years 97.3% overnight.
Dual hormone
Castle et al. Insulin + Randomized N = 20 4 days Addition of glucagon with automated exercise
(2018) [65] glucagon crossover Age 21–45 years detection reduced hypoglycemia (3.4 vs. 8.3%
during exercise; 1.3 vs. 2.8% for entire study)
Haidar et al. Insulin + Randomized N = 28 Three 24-h Rapid insulin +pramlintide system increased TIR
(2020) [39] pramlintide crossover Mean age 25 years inpatient visits compared to insulin only (84 vs. 74%) due to
improved daytime control. Most common AE
from pramlintide was gastrointestinal issues.

AP, artificial pancreas; RCT, randomized controlled trial; TIR, time in rage (70–180 mg/dL); HCL, hybrid closed loop; CGM, continuous glucose
monitor; SAP, sensor-augmented pump; e-HCL, enhanced hybrid closed-loop; AE, adverse event

received a mean of 0.72 mg of glucagon (i.e., the majority of a
standard rescue dose of 1 mg) each day. A similar study in
children 6–11 years old found that TIR in this group on the
dual-hormone system (vs. usual care) increased to 80.6% ±
7.4 from 57.6% ± 14.0, with a decrease in time < 70 mg/dL
(2.9 vs. 6.1%) [36]. These younger children received a mean
of 0.36 mg of glucagon daily. More recently, this research
group also published a pilot study that directly compared an
insulin-only with the dual-hormone system among adults with
cystic-fibrosis-related diabetes, finding similar glycemic con-
trol (TIR 70–180 mg/dL for glucagon-insulin system vs. in-
sulin only; 80% ± 10 vs. 76% ± 9, p not significant) [37].
Another study in adults found that while the glucagon-
insulin provided higher TIR during use compared to usual
care (78.4 vs. 61.9%), a visual analogue scale revealed signif-
icantly higher scores for nausea during dual-hormone use
[38•]. Overall, given that dual-hormone systems (as compared
to insulin-only AP systems) appear to provide similar glyce-
mic control but more nausea, it remains unclear what their role
will be in pediatric AP control in the future.
Other researchers assessing dual-hormone AP systems
have co-infused insulin and pramlintide, an analogue of
amylin, which is secreted by pancreatic beta cells post-
prandially, resulting in slower gastric emptying and inhibition
of glucagon. Studies in adults have demonstrated that
pramlintide-insulin systems produce improvements over insu-
lin alone (TIR 84 vs. 74%), but these have not been tested in
pediatrics [39].
Mobile Interoperable Closed-Loop Platforms
The currently available AP systems run from algorithms em-
bedded into the insulin pump; however, a potential alternative
would be to run the system on a mobile platform using a
smartphone. As previously discussed, early AP research was
conducted in this manner and the first platform developed, the
Diabetes Assistant (DiAS), was developed at the University of
Virginia [40, 41]. Benefits of using a smartphone include that
they are widely available, easy to upgrade, can offer a more
detailed user interface, and could potentially work with mul-
tiple different CGM and insulin pump devices for user
customizability. However, inconsistent wireless connectivity
may be a key limitation. Multiple mobile closed-loop plat-
forms are currently under investigation, FlorenceM
54
(Cambridge algorithm), inControl AP, and Interoperable
Artificial Pancreas System (iAPS). These systems have been
studied in clinical trials of varying sizes, and have also shown
promise in improving glycemic control [42–44].
Patient-Reported Outcomes
In addition to improved glycemic outcomes, AP systems have
been shown to decrease the burden of diabetes management
and increase quality of life, although this is an area in need of
further study. Barnard et al. reported reduced worry, improved
overnight control leading to improved daily functioning, and
improved sleep in AP users, although technical and connec-
tivity issues and intrusive alarms were cited as negative expe-
riences [45]. In the field of pediatrics, these outcomes are of
interest not only for children with T1D but also for their par-
ents. Studies of parents of young children with T1D on AP
systems have reported reduced burden of diabetes manage-
ment, less worry, and improved quality of sleep [46]. The
durability of these effects in longer-term studies remains to
be seen.
Barriers to AP Use
Despite documented improved glycemic outcomes with use of
diabetes technology, barriers to use remain. A recent study by
Messer et al. noted that cost and insurance coverage were the
most commonly cited barriers to the use of technology in over
400 adolescents surveyed with T1D [47]. Additional signifi-
cant barriers reported included the hassle of wearing devices
and disliking the device on their body. Additionally, some
adolescent subjects reported that they were nervous that the
device might not work adequately or safely, that it would
actually increase the time required to manage their diabetes,
and that using the system would influence how others individ-
uals think of them.
Future Directions
Postprandial hyperglycemia is responsible for the majority of
time spent out of range on HCL systems. In addition to devel-
oping accurate meal-detection algorithms to achieve a fully
automated system, improved insulin analogs with a more rap-
id onset and a shorter duration of action will likely be neces-
sary to improve control of postprandial glycemic excursions.
As previously noted, the amylin analogue pramlintide is also
being studied as a method to decrease glycemic excursions
related to meals. Additionally, work is being done to allow
for increased individualization and adaptation of AP systems
to changes in insulin sensitivity throughout the day.
Curr Nutr Rep (2021) 10:47–57
The development of a fully automated AP system remains
the goal given the burden of carbohydrate counting and sig-
nificant contribution of missed meal boluses to poor glycemic
control. A few small studies evaluating fully automated insu-
lin delivery have been published with moderately encouraging
results [48–51]; however, there have been no large outpatient
trials to date and mean glucose appears to be lower when
using a HCL system with pre-meal announcement at this time.
While the majority of children with T1D are not using AP
systems at this time, automated insulin delivery is quickly
becoming the standard of care for those using insulin pumps,
and it is possible that AP systems will become the dominant
approach to diabetes control for all people with T1D over
time.
Conclusion
Diabetes technology has advanced significantly over the past
decade, allowing for improved therapies for people living with
type 1 diabetes and hope for better quality of life, less burden
of care, and decreased risk of diabetes-related complications.
Hybrid closed-loop AP systems have consistently been found
to be safe and effective in improving glycemic outcomes,
particularly overnight, across all populations studied including
young children. As algorithms become more advanced, the
ultimate goal of a fully automated system feels within reach.
Compliance with Ethical Standards
Conflict of Interest MJS has had grant support from Tandem Diabetes
Care, Inc.; Medtronic, PLC; and Insulet Corporation. MDD has had grant
or material support from Tandem Diabetes Care, Inc.; Medtronic, PLC;
and DexCom, Inc.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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